It is estimated that in the United States alone, there are between 10 and 20 million men with moderate to severe forms of erectile dysfunction. An additional 10 million men exist for whom urinary tract dysfunction is also a significant problem.
Penile erection and detumescence involve a complex interaction of direct neuronal activation combined with the release of endothelial derived contractile and relaxant factors. A variety of neurotransmitter substances and vasoactive modulators have been described. Of these, nitric oxide appears to play a primary role in the development of an erection.
Cavernosal smooth muscle relaxation is one of the primary events in penile erection. Although it is believed to be initiated by the synthesis and release of NO from nonadrenergic-noncholinergic neurons of the corpus cavernosum (Kimura et al., Nippon Hinyokika Gakkai Zasshi 84(9): 1660-1664 (1993); Rajfer et al., N. Engl. J. Med. 326(2): 90-94 (1992); Knispel et al., Urol. Res. 20(4): 253-257 (1992); Burnett et al., Science 257(5068): 401-403 (1992); and Mills et al., Biol. Reprod. 46(3): 342-348 (1992)), studies undertaken to determine whether or not the serum levels of NO metabolites, i.e, nitrites and nitrates, increase in peripheral and cavernosal blood during penile erection in potent adult humans demonstrated that nitrite and nitrate levels do not change appreciably during and immediately following erection (Moriel et al., Urology 42(5): 551-553 (1993)). Physiological concentrations of oxygen in the corpus cavernosum tissue, however, are believed to modulate penile erection by regulating NO synthesis (Kim et al., J. Clin. Invest. 91(2): 437-442 (1993)). It has been further hypothesized that relaxation of the corpus cavernosum, initiated in response to nitric oxide synthesis and release from nonadrenergic-noncholinergic neurons, could be amplified and maintained by NO production as a result of platelet trapping in the corpus cavernosum during the first phase of penile erection (Alberti et al., Minerva Urol. Nefrol. 45(2): 49-54 (1993)).
Currently available therapies for erectile dysfunction include needle injection of a vasodilator drugs directly into the penis; a vacuum constriction device (VCD), which pulls blood into the penis and holds it there with a constriction ring; a surgical implant, which provides rigidity; oral medication, such as yohimbine, which appears to have beneficial effects in only a small proportion of patients; psychological therapy, for which few data exist on long term benefit; and vascular surgery, which is appropriate in only a very small number of patients. All six therapies have significant drawbacks. In fact, they are so limited in appeal that fewer than ten percent of men with erectile dysfunction have adopted any one of the therapies at all. In addition, each of these therapies suffers from exceedingly high rates of discontinuance for reasons that are not entirely related to the therapy, itself. There remains a need, therefore, for an effective method of treating impotency.
Nitric oxide has been utilized as a means of studying penile erection and penile dysfunction due to diabetes and venous leakage, for example. The potential usefulness of nitric oxide to treat impotence has been discussed by McGuffey (Am. Pharm. NS33(7): 20 (1993)).
Nitric oxide in its pure form, however, is a highly reactive gas having limited solubility in aqueous media (WHO Task Group on Environmental Health Criteria for Oxides of Nitrogen, Oxides of Nitrogen, Environmental Health Criteria 4 (World Health Organization: Geneva, 1977)). Nitric oxide, therefore, is difficult to introduce reliably into most biological systems without premature decomposition.
A number of compounds have been developed that are capable of delivering nitric oxide in a pharmacologically useful way. Such compounds include compounds that release nitric oxide upon being metabolized and compounds that release nitric oxide spontaneously in aqueous solution.
Compounds that release nitric oxide upon being metabolized include the widely used nitrovasodilators glyceryl trinitrate and sodium nitroprusside (SNP) (Ignarro et al., J. Pharmacol. Exp. Ther., 218, 739-749 (1981); Ignarro, Annu. Rev. Pharmacol. Toxicol., 30, 535-560 (1990); Kruszyna et al., Toxicol. Apol. Pharmacol., 91, 429-438 (1987); Wilcox et al., Chem. Res. Toxicol., 3, 71-76 (1990)), which are relatively stable but release nitric oxide on activation. While this feature may be an advantage in some applications, it also can be a significant liability. For example, tolerance to glyceryl trinitrate can develop via the exhaustion of the relevant enzyme/cofactor system (Ignarro et al., Annu. Rev. Pharmacol. Toxicol., 25, 171-191 (1985); Kuhn et al., J. Cardiovasc. Pharmacol., 14 (Suppl. 11), S47-S54 (1989)). Also, prolonged administration of nitroprusside results in the metabolic production of cyanide, which leads to toxicity (Smith et al., "A Potpourri of Biologically Reactive Intermediates" in Biological Reactive Intermediates IV. Molecular and Cellular Effects and Their Impact on Human Health (Witmer et al., eds.), Advances in Experimental Medicine and Biology Volume 283 (Plenum Press: New York, 1991), pp. 365-369). S-Nitroso-N-acetylpenicillamine (SNAP) has been reported to release nitric oxide in solution and to be effective at inhibiting DNA synthesis (Garg et al., Biochem. and Biophys. Res. Comm., 171, 474-479 (1990)).
SNP has been administered to primates for purposes of studying the physiology and pharmacology of erection (Hellstrom et al., J. Urol. 151(60: 1723-1727 (1994)). Intracavernosal injection of SNP induced erections with dose-dependent increases in cavernosal pressure and penile length.
The NO donor linsidomine chlorohydrate, otherwise known as 3-morpholinosydnonimine or SIN-1, was administered to 30 human patients with erectile dysfunction caused by venous leakage (Wegner et al., Urology 42(4): 409-411 (1993)) and was less effective than prostaglandin E1 (PGE1) in treating the dysfunction in over two-thirds of the patients treated. SIN-1 was also found to be less effective than SNP in relaxing isolated rabbit corpus cavernosum (Holmquist et al., J. Urol. 150(4): 1310-1315 (1993)). More promising results with SIN-1 were obtained in a 63-patient study carried out by Stief et al. (J. Urol. 148(5): 1437-1440 (1992)). However, activation of SIN-1 by oxygen produces both NO and superoxide ion, two species that can combine with one another to produce the potent oxidant, ONOO.sup.-. The potential to produce this toxic by-product is believed to limit the utility of such sydnonimine drugs.
Numerous nitric oxide-nucleophile complexes also have been described, e.g., by Drago, ACS Adv. Chem. Ser., 36, 143-149 (1962). See also Longhi and Drago, Inorg. Chem., 2, 85 (1963). Some of these complexes, known as NONOates, evolve nitric oxide on heating or hydrolysis (Maragos et al., J. Med. Chem., 34, 3242-3247 (1991)).
These compounds contain the anionic N.sub.2 O.sub.2.sup.- group or derivatives thereof. Many of these compounds have proven especially promising pharmacologically because, unlike SNP and nitroglycerin, they release NO without first having to be activated. The only other series of drugs currently known to be capable of releasing NO purely spontaneously is the S-nitrosothiol series, compounds of structure R--S--N.dbd.O (Stamler et al., Proc. Natl. Acad. Sci. U.S.A., 89, 444-448 (1992)); however, the R--S--N.dbd.O.fwdarw.NO reaction can be kinetically complicated and difficult to control (Morley et al., J. Cardiovasc. Pharmacol., 21, 670-676 (1993)), and extensive redox activation (McAninly et al., J. Chem. Soc., Chem. Comm., 1758-1759 (1993)) and metabolism (Kowaluk et al., J. Pharmacol. Exp. Ther., 255, 1256-1264 (1990)) have been documented for these compounds. Moreover, the oxidation state of nitrogen in the S-nitrosothiols is +3, rather than the +2 of nitric oxide. While variation in the R group of the R--S--N.dbd.O compounds provides a means of altering their chemical, and hence pharmacological, properties, the NONOate series is especially versatile in this respect. NONOates having reproducible half-lives ranging from 2 seconds to 20 hours have been prepared. They can be O-alkylated to provide either spontaneous NO-generators with half-lives of up to a week or more or prodrugs that cannot release NO at all until the oxygen substituent is removed metabolically. The NONOate function can be coordinated via the two oxygen atoms to metal centers; it can be attached to natural products, such as spermine (a constituent of human semen) and peptides; and it can be bound in solid polymeric matrices to provide a point source of NO. A compound containing more than one nucleophile residue (such as, for example, the polyamine, spermine) can be bound to more than one NONOate group, to thereby provide a single NONOate molecule with bi- or polyphasic NO release rates. By providing such a wide variety of NO release rates, physical forms, and potential strategies for targeting NO delivery to specific sites in the body, the NONOates constitute a most advantageous series of compounds on which to base NO donor drug development efforts.
Nitric oxide/nucleophile complexes (NONOates) that release nitric oxide in aqueous solution are disclosed in U.S. Patent Nos. 4,954,526, 5,039,705, 5,155,137, 5,185,376, 5,208,233, 5,212,204, 5,250,550, 5,366,977, and 5,389,675, as being useful cardiovascular agents (see also Maragos et al., J. Med. Chem., 34, 3242-3247 (1991)).
Despite the promise of the nitric oxide/nucleophile complexes that have been described thus far in the literature, their pharmacological application is limited by their tendency to distribute evenly throughout the medium. Such even distribution is a great advantage in many applications, but tends to compromise their selectivity of action. However, the nitric oxide/nucleophile complexes can be incorporated into polymers in order to overcome this limitation by enabling concentrated and localized release of NO at a given site in a controllable and predictable manner such that effective dosing can be realized. This imparts a tremendous advantage to the technology for the treatment of erectile dysfunction.
The present invention provides a method of treatment for impotency in a male animal that overcomes the above-described disadvantages of currently available treatment methods by employing NONOates as nitric oxide-releasing agents in the form of polymers, pharmaceutical compositions, and various delivery means comprising such compositions and polymers. Accordingly, the present invention also seeks to provide delivery means for use in the present inventive method. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.